AIDS was first clinically observed in 1981, and HIV (Human Immunodeficiency Virus) was discovered as causing AIDS as it was isolated from AIDS patients in 1984.
Taxonomically, HIV is a member of the genus Lentivirus, part of the family of Retroviridae. An HIV particle is roughly spherical with a diameter of about 10 microns. Its genome is composed of two copies of RNA enclosed by a protein sac (capsid, core protein) which is, in turn, surrounded by a viral envelope composed of phospholipids, like general plasma membranes. The HIV genome codes for 10 genes, which are too many relative to the total size of the genome.
HIV infection is mediated through interaction of the envelope glycoproteins (gp120) on the viral surface with receptors on the target cell. The cell surface protein molecules that act as the receptors are mainly CD4 antigens. This is why cells that express CD4 on their surface (CD4+ cells), such as macrophages and helper T cells, are the main target cells of HIV. Following the adsorption of the glycoprotein to the receptors, the viral phospholipid envelope is fused with the cell membrane with the concomitant release of the HIV genome and nucleocapsid into the cell. Upon entry into the target cell, the viral RNA genome is converted into DNA by a virally encoded reverse transcriptase that is transported along with the viral genome in the virus particle. The viral DNA is then transported into the cell nucleus and integrated into the host cell's genome. This procedure is one of the unique features that retroviruses have. As such, the integrated viral DNA lies dormant in the safest site of the host cell while being supplied with all mechanisms and resources necessary for the growth of the virus from the cell. Further, HIV protects itself from and survives the immune system while proliferating or entering the latent stage of infection depending on surrounding situations and conditions.
Two types of AIDS viruses are characterized: HIV-1 and HIV-2. HIV-1 is found in patients all over the world and is the cause of the majority of HIV infections globally. HIV-2 is largely confined to West Africa. Its nucleotide sequence is only 55% identical to that of HIV-1, and rather more similar to that of SIV (Simian Immunodeficiency Virus), known as monkey AIDS virus. HIV-2 is less virulent than HIV-1. HIV not only has very high biological variability, but also very high genetic variability. The nucleotide sequences of HIV differ from one AIDS patient to another, and vary with the progress of AIDS even in the same patient. What is more serious, the nucleotide sequences of HIV, when sampled at the same time from the same patient, are different depending on sampling tissue. These HIV sequence polymorphisms are strongly associated with various biological characteristics of the virus. Given different nucleotide sequences, HIV differs in target cell preference for its infection, virion productivity, cytotoxicity, ability to form multinucleated giant cells, latent period and active period, and sensitivity to neutralizing antibodies. More recent studies on the relationship between variable biological properties of HIV and pathogenesis of HIV infection show that most AIDS viruses isolated from patients in the early stages do not create multinucleated giant cells (nonsyncytia-inducing (NSI)) and prefer macrophages for their infection, whereas HIV is increasingly liable to create multinucleated giant cells (syncytia-inducing (SI)), and replicate preferably in T-helper cells, with the progression of AIDS, indicating that there is strong relationship between biological properties of HIV and pathogenesis of HIV infection.
One week after HIV infection, the virus actively proliferates and can be easily detected in the blood of the infectee, that is, he or she becomes viremic. Then, the virus rapidly decreases to such a low level within one to two weeks that it cannot be isolated. After maintenance of such latency for a significant period of time, HIV actively replicates with the onset of AIDS, so that viremia occurs. Recent PCR research has attracted attention because of its report that HIV replicates while it is dormant. After HIV infection, the level of CD4 cells rapidly decreases during the primary viremia period, and then is recovered to a constant value (healthy person: 500-1000 CD4 cells/mm2). Since that point, the blood level of CD4 cells gradually decreases over several years. When CD4 cells drop below 200 counts per mm3 of blood, the onset of ARC (AIDS-related complex) or AIDS takes place. AIDS patients experience a condition in which progressive failure of the immune system allows life-threatening opportunistic infections, such as Pneumocysitis carinii pneumonia, to thrive. The time period during which the HIV level rapidly reduces after the primary viremia is incident with the activation period of CD8 cells. CD8 T cells are known to act to inhibit cell growth or selectively kill virus-infected cells. Hence, CD8 T cells seem to account for immunity against the early infection virus. Antibodies are produced after the virus level is reduced. CD8 cells and antibodies continue to exist during the time period from the initial time of infection to the onset of AIDS, but their functions have been reduced, or denatured, and they even promote the HIV infection. How the immune system that exhibits apparent anti-viral activity in the early stage of infection is lost remains a problem that is yet to be solved. Due to AIDS specificity for humans, the understanding of the etiology of HIV is at an extremely low level. Although there is consensus among scientists about the fact that a reduction in CD4 cell level is a direct cause of immunodeficiency, there are various different opinions on how HIV reduces the level of CD4 cells. Suggested theories accounting for the reduction of CD4 cell level include the formation of multinucleated giant cells, the accumulation of non-inserted viral DNA, influence on the structure of host cell membranes, the induction of programmed cell death, the secretion of toxic matter from infected cells, and autoimmune-mediated cytolysis. None of them, however, have thus far been proven as fact, or have been shown to occur in practice in vivo. Extensive research into HIV pathogenesis has been conducted on monkeys using the monkey AIDS virus SIV, but it has yielded no novel findings.
Most prevalent among currently available AIDS drugs is AZT (zidovudine), which is an HIV reverse transcriptase inhibitor. It remains in widespread use today and is recognized as one of the most effective drugs in medical history. This drug is clinically very effective in the early stages of HIV infection, but is found to have no positive influences on the extension of a patient's life because of its side effects. That is, AZT induces bone marrow toxicity, and may allow HIV to become AZT-resistant over time. DDI, DDC, and d4T, all functioning like AZT, and approved by the FDA, are found to be less toxic than AZT, but induce HIV to be resistant thereto.
There are many anti-viral methods that have been developed that are awaiting efficacy testing. Examples of them are the prevention of viral adsorption to cells, the selective killing of virus-infected cells, the use of inhibitors against enzymes playing an important role in viral growth (e.g., protease, integrase, tat inhibitor, rev inhibitor, etc.), cytokine therapies, injection of CD8 cells, and gene therapies. There has also been a great advance in the development of HIV vaccines, such as the use of a dead virus, or attenuated virus, which is alive but not pathogenic, an isolated viral protein expressed by bioengineering (subunit vaccine), an anti-idiotypic antibody, and the direct injection of a DNA gene. However, a fundamental problem with the development of vaccines lies in the excessive diversity of HIV viruses. For example, a person immunized with a vaccine is observed to inhibit the virus used for developing the vaccine when challenged with the same virus, but does not exhibit immunoprotection at all when challenged with the infected cells or viruses taken from a different patient. This viral diversity also remains as a problem yet to be solved.
There is therefore a pressing need for an AIDS drug that overcomes the problems encountered in the prior arts, including side effects and resistant viruses of conventional AIDS therapeutics.